Understanding physical mechanism of low-level microwave radiation effect.

PURPOSE: This topic review aims to explain the mechanism of low-level microwave (MW) radiation effect based on published research results. The review presents the analysis of theoretical and experimental results comprising underlying physics and derived biological-physiological consequences supported by experimental data. CONCLUSIONS: The rotation of dipolar molecules causes polarization of dielectric medium and restructuring of hydrogen bonds between these molecules. The weakened hydrogen bonds decrease viscosity and enhance diffusion at constant temperature. All steps of proposed model have no critical frequency restrictions at MW frequencies and have been confirmed by electromagnetic field (EMF) theory and/or published experimental results. The synchronous cumulative impact of coherent MW electric field makes possible the field-induced effect despite the field strengths are much weaker than intermolecular fields. The rotation of dipolar molecules results in restructuring hydrogen bonds between the molecules despite the energy of MW radiation is much less than the energy of bonding. The cumulative impact of coherent MW field in a medium has been convincingly confirmed by the measurable dielectric permittivity of the medium. The described mechanism of MW field-induced effect confirms that the nature of the effect differs from the thermal effect and that the exposure by MW radiation can create the specific consequences in biology and materials not characteristic for conventional heating.

Influence of extrinsic operational parameters on salt diffusion during ultrasound assisted meat curing.

The present study investigated the effect of geometric parameters of the ultrasound instrument during meat salting in order to enhance salt diffusion and salt distribution in pork meat on a lab scale. The effects of probe size (∅2.5 and 1.3cm) and of different distances between the transducer and the meat sample (0.3, 0.5, and 0.8cm) on NaCl diffusion were investigated. Changes in the moisture content and NaCl gain were used to evaluate salt distribution and diffusion in the samples, parallel and perpendicular to ultrasound propagation direction. Results showed that 0.3cm was the most efficient distance between the probe and the sample to ensure a higher salt diffusion rate. A distance of 0.5cm was however considered as a trade-off distance to ensure salt diffusion and maintenance of meat quality parameters. The enhancement of salt diffusion by ultrasound was observed to decrease with increased horizontal distance from the probe. This study is of valuable importance for meat processing industries willing to apply new technologies on a larger scale and with defined operational standards. The data suggest that the geometric parameters of ultrasound systems can have strong influence on the efficiency of ultrasonic enhancement of NaCl uptake in meat and can be a crucial element in determining salt uptake during meat processing.

Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phantoms, and the constructs were treated daily for 14 days with ultrasound at 2.2 W/cm2 for 10 min. The 2D distribution of fluorescein within the phantoms was quantified using fluorescence imaging. Implants receiving ultrasound irradiation showed a 1.7-5.6 fold increase (p < 0.05) in fluorescence intensity and penetration distance, with the maximum increase observed 5 days post-implantation. However, this evidence was not seen when the same experiment was also carried out in phosphate buffer saline (pH 7.4). Results suggest an active role of ultrasound in local molecular transport in the phantom. An increase of fluorescein release and penetration depth in phantoms can be accomplished through brief application of ultrasound. This simple technique offers an opportunity to eventually enhance the therapeutic efficacy and broaden the application of local drug delivery systems.

Vitamin E-stabilized highly crosslinked polyethylenes: The role and effectiveness in total hip arthroplasty.

Morphology and design of ultra-high molecular weight polyethylene (UHMWPE or simply PE) acetabular components used in total hip arthroplasty (THA) have been evolving for more than half a century. Since the late-1990s, there were two major technological innovations in PE emerged from necessity to overcome the wear-induced periprosthetic osteolysis, i.e., the development of highly crosslinked PEs (HXLPEs). There are many literature reporting that radiation crosslinked and remelted/annealed (first-generation) HXLPEs markedly reduced the incidence of osteolysis and aseptic loosening. Regardless of such clinical success in the first-generation technologies, there were some recent shifts in Japan toward the use of new second-generation HXLPEs subjected to sequential irradiation/annealing or antioxidant vitamin E (α-tocopherol) incorporation. Although the selection rate of first-generation liners still account for more than half of all the PE THAs (∼58% in 2015), the use of vitamin E-stabilized liners has been steadily growing each year since their clinical introduction in 2010. In these contexts, it is of great importance to evaluate and understand the real clinical benefits of using the new second-generation liners as compared to the first generation. This article first summarizes structural evolution and characteristic features of first-generation HXLPEs, and then provides a detailed description of second-generation antioxidant HXLPEs in regard to the role of vitamin E incorporation on their chemical and mechanical performances in THA.

A thermo-degradable hydrogel with light-tunable degradation and drug release.

The development of thermo-degradable hydrogels is of great importance in drug delivery. However, it still remains a huge challenge to prepare thermo-degradable hydrogels with inherent degradation, reproducible, repeated and tunable dosing. Here, we reported a thermo-degradable hydrogel that is rapidly degraded above 44 °C by a facile chemistry. Besides thermo-degradability, the hydrogel also undergoes rapid photolysis with ultraviolet light. By embedding photothermal nanoparticles or upconversion nanoparticles into the gel, it can release the entrapped cargoes such as dyes, enzymes and anticancer drugs in an on-demand and dose-tunable fashion upon near-infrared light exposure. The smart hydrogel works well both in vitro and in vivo without involving sophisticated syntheses, and is well suited for clinical cancer therapy due to the high transparency and non-invasiveness features of near-infrared light.

Conducting polymers with defined micro- or nanostructures for drug delivery.

Conducting polymers (CPs) are redox active materials with tunable electronic and physical properties. The charge of the CP backbone can be manipulated through redox processes, with accompanied movement of ions into and out of the polymer to maintain electrostatic neutrality. CPs with defined micro- or nanostructures have greatly enhanced surface areas, compared to conventionally prepared CPs. The resulting high surface area interface between polymer and liquid media facilities ion exchange and can lead to larger and more rapid responses to redox cycling. CP systems are maturing as platforms for electrically tunable drug delivery. CPs with defined micro- or nanostructures offer the ability to increase the amount of drug that can be delivered whilst enabling systems to be finely tuned to control the extent and rate of drug release. In this review, fabrication approaches to achieve CPs with micro- or nanostructure are outlined followed by a detailed review and discussion of recent advances in the application of the materials for drug delivery.

Guidance of Magnetic Nanocontainers for Treating Alzheimer's Disease Using an Electromagnetic, Targeted Drug-Delivery Actuator.

The "impermeability" of the blood-brain barrier (BBB) has hindered effective treatment of central nervous system (CNS) disorders such as Alzheimer's disease (AD), which is one of the most common neurodegenerative disorders. A drug can be delivered to a targeted disease site effectively by applying a strong electromagnetic force to the conjugate of a drug and magnetic nanocontainers. This study developed a novel nanotechnology-based strategy to deliver therapeutic agents to the brain via the BBB as a possible therapeutic approach for AD. First, a novel approach for an electromagnetic actuator for guiding nanocontainers is introduced. Then, we analyzed the in vivo uptake in mice experimentally to evaluate the capacity of the nanocontainers. In the mouse model, we demonstrated that magnetic particles can cross the normal BBB when subjected to external electromagnetic fields of 28 mT (0.43 T/m) and 79.8 mT (1.39 T/m). Our study also assessed the differential effects of pulsed (0.25, 0.5, and 1 Hz) and constant magnetic fields on the transport of particles across the BBB in mice injected with magnetic nanoparticles (MNPs) via a tail vein. The applied magnetic field was either kept constant or pulsed on and off. Relative to a constant magnetic field, the rate of MNP uptake and transport across the BBB was enhanced significantly by a pulsed magnetic field. Localization inside the brain was established using fluorescent MNPs. These results using 770-nm fluorescent carboxyl magnetic nanocontainers demonstrated the feasibility of the proposed electromagnetic targeted drug delivery actuator. These results establish an effective strategy for regulating the biodistribution of MNPs in the brain through the application of an external electromagnetic field. This might be a valuable targeting system for AD diagnosis and therapy.

Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration.

Chemotherapeutic drug delivery is often ineffective within solid tumors, but increasing the drug dose would result in systemic toxicity. The use of high-intensity focused ultrasound (HIFU) has the potential to enhance penetration of small molecules. However, operation parameters need to be optimized before the use of chemotherapeutic drugs in vivo and translation to clinical trials. In this study, the effects of pulsed HIFU (pHIFU) parameters (spatial-average pulse-average intensity, duty factor and pulse repetition frequency) on the penetration as well as content of small molecules were evaluated in ex vivo porcine kidneys. Specific HIFU parameters resulted in more than 40 times greater Evans blue content and 3.5 times the penetration depth compared with untreated samples. When selected parameters were applied to porcine kidneys in vivo, a 2.3-fold increase in concentration was obtained after a 2-min exposure to pHIFU. Pulsed HIFU has been found to be an effective modality to enhance both the concentration and penetration depth of small molecules in tissue using the optimized HIFU parameters. Although, performed in normal tissue, this study has the promise of translation into tumor tissue.

A pH-Driven and photoresponsive nanocarrier: Remotely-controlled by near-infrared light for stepwise antitumor treatment.

The hollow gold nanospheres (HAuNS) have shown medicinal promise due to their inert and nontoxic properties with unique photothermal therapy capabilities. In this study, the electrostatic approach was employed to successfully absorb Chlorin e6 (Ce6) simultaneously with the pH (low) insertion peptide (pHLIP) onto surface of HAuNS, forming HAuNS-pHLIP-Ce6 with desirable pH-driven and NIR light-stimulated controlled therapeutical effect. The HAuNS-pHLIP-Ce6 experienced hyperthermia within 5 min of laser exposure, which marked the photothermal therapy (PTT) and deduced the agents release due to the reduction of electrostatic interaction. The improved strategy facilitated a stepwise photoresponsive system capable of active accumulation and retention effects, photothermal ablation of tumor cells, release of photosensitizers (PS), and subsequently photodynamic therapy (PDT) in a single light irradiation session. The smart delivery system had been proved with multi-functionalities via conjugated targeting ligand and PS. The external absorption of patient tailored medication combinations was also possible with this treatment platform.

Characterization and Insights Into the Nano Liposomal Magnetic Gene Vector Used for Cell Co-Transfection.

The development of magnetofection technology has brought a promising method for gene delivery. Here, we develop a novel liposomal magnetofection system, consisted of magnetic nanoparticle and liposome through molecular assembly, was applied to introduce double genes into porcin somatic cells with high co-transfection efficiency. The performace of liposomal magnetic gene nanovectors has been evaluated by involving the micro morphology, diameters distribution, zeta potentials and the capacity of loading DNA molecules. The assembly way among magnetic gene nanovectors and DNA molecules was investigated by atomic force microscopy. Liposomal nano magnetic gene vectors complexes displayed nanoscale assembly and formed compact "fishing-net structure" after combining with plasmid DNA, which is favorable to enhance the loading capacity of DNA molecules.

Nano "Chocolate Waffle" for near-IR Responsive Drug Releasing System.

A majority of the photo-responsive drug-delivery systems that are currently being studied require a complicated synthesis method. Here, we prepare a near-infrared responsive, photothermally controllable, drug-delivery carrier by a simple mixing and extraction process without the incorporation of toxic chemicals. A blend of doxorubicin (DOX), an anticancer drug, and a phase-change material (PCM) are loaded onto the mesoporous structure of silica-coated graphene oxide (GO@MS) to form a waffle-like structure, which is confirmed by various physicochemical analyses. The cytotoxicity of DOX/PCM-loaded GO@MS (DOX/PCM-GO@MS) against HeLa cells is 50 times higher than that of free DOX, and this improved activity can be attributed to the photothermal effectiveness of GO@MS. Additionally, the cytotoxicity and uptake mechanism of the PCM-based material are analyzed by flow cytometry. Taken together, our results suggest an enormous potential for spatio-temporal control in photothermally responsive drug-delivery systems.

The effect of region of interest strategies on apparent diffusion coefficient assessment in patients treated with palliative radiation therapy to brain metastases.

BACKGROUND: Although diffusion-weighted magnetic resonance imaging (DW-MRI) is widely used in radiation therapy (RT) response studies, no standard of delineating the region of interest (ROI) exists. In this retrospective study, we evaluate the effect of four ROI strategies on the apparent diffusion coefficients (ADC) in patients receiving palliative RT to brain metastases. MATERIAL AND METHODS: Twenty-two metastases from nine patients, treated with whole-brain irradiation (30 Gy in 10 fractions) were analyzed. Patients were scanned with a 1T MR system to acquire DW- (eight b-values), T2*W-, T2W- and T1W scans, before start of RT (pre-RT) and at the 9th/10th fraction (end-RT). The following ROI strategies were applied. ROIb800 and ROIb0: Entire tumor volume visible on DW(b = 800 s/mm(2)) and DW(b = 0 s/mm(2)) images, respectively. ROIb800vi: Viable tumor volume based on DW(b = 800 s/mm(2)). ROIb800rep: ROIb800 from pre-RT scan replicated to end-RT scan. Delineations were aided by co-registered T1W, T2W and T2*W images. ADC was estimated with two mono-exponential fits and one bi-exponential fit. RESULTS: Differences in absolute ADC values were non-significant across ROI strategy independent of fitting method, while significantly different between fitting methods. Evaluation of individual metastases showed that ROI strategies disagreed on the relative ADC change (from pre-RT to end-RT) in 13 of the 22 metastases when all fitting methods were added up. CONCLUSION: The ROI strategies have an effect on the relative ADC change, which may be important for the assessment of individual patient's response to RT and the interpretation of the current literature.

Diffusion-weighted magnetic resonance imaging during radiotherapy of locally advanced cervical cancer--treatment response assessment using different segmentation methods.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) and the derived apparent diffusion coefficient (ADC) value has potential for monitoring tumor response to radiotherapy (RT). Method used for segmentation of volumes with reduced diffusion will influence both volume size and observed distribution of ADC values. This study evaluates: 1) different segmentation methods; and 2) how they affect assessment of tumor ADC value during RT. MATERIAL AND METHODS: Eleven patients with locally advanced cervical cancer underwent MRI three times during their RT: prior to start of RT (PRERT), two weeks into external beam RT (WK2RT) and one week prior to brachytherapy (PREBT). Volumes on DW-MRI were segmented using three semi-automatic segmentation methods: "cluster analysis", "relative signal intensity (SD4)" and "region growing". Segmented volumes were compared to the gross tumor volume (GTV) identified on T2-weighted MR images using the Jaccard similarity index (JSI). ADC values from segmented volumes were compared and changes of ADC values during therapy were evaluated. RESULTS: Significant difference between the four volumes (GTV, DWIcluster, DWISD4 and DWIregion) was found (p < 0.01), and the volumes changed significantly during treatment (p < 0.01). There was a significant difference in JSI among segmentation methods at time of PRERT (p < 0.016) with region growing having the lowest JSIGTV (mean± sd: 0.35 ± 0.1), followed by the SD4 method (mean± sd: 0.50 ± 0.1) and clustering (mean± sd: 0.52 ± 0.3). There was no significant difference in mean ADC value compared at same treatment time. Mean tumor ADC value increased significantly (p < 0.01) for all methods across treatment time. CONCLUSION: Among the three semi-automatic segmentations of hyper-intense intensities on DW-MR images implemented, cluster analysis and relative signal thresholding had the greatest similarity to the clinical tumor volume. Evaluation of mean ADC value did not depend on segmentation method.

Ultrasonically Assisted Polysaccharide Microcontainers for Delivery of Lipophilic Antitumor Drugs: Preparation and in Vitro Evaluation.

High toxicity, poor selectivity, and severe side effects are major drawbacks of anticancer drugs. Various drug delivery systems could be proposed to overcome these limitations. The aim of this study was to fabricate polysaccharide microcontainers (MCs) loaded with thymoquinone (TQ) by a one-step ultrasonication technique and to study their cellular uptake and cytotoxicity in vitro. Two MC fractions with a mean size of 500 nm (MC-0.5) and 2 µM (MC-2) were prepared and characterized. Uptake of the MCs by mouse melanoma M-3 cells was evaluated in both 2D (monolayer culture) and 3D (multicellular tumor spheroids) models by confocal microscopy, flow cytometry, and fluorimetry. The higher cytotoxicity of the TQ-MC-0.5 sample than the TQ-MC-2 fraction was in good correlation with higher MC-0.5 accumulation in the cells. The MC-0.5 beads were more promising than the MC-2 particles because of a higher cellular uptake in both 2D and 3D models, an enhanced antitumor effect, and a lower nonspecific toxicity.

Quantitative evaluation of sonophoresis efficiency and its dependence on sonication parameters and particle size.

Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%-100%; acoustic intensity, 0.3-1.0 W/cm(2); duration, 7-30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean ± SD, 62.6% ± 5.4% for 60-nm versus 11.9% ± 1.1% for 840-nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm(2) and a 100% duty cycle; P < .05). On scanning electron microscopy the pore size remained the same (≈100 µm), but more flakes were observed with the progress of sonication. In summary, sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores.

Hydrogel patterning by diffusion through the matrix and subsequent light-triggered chemical immobilization.

A novel approach to hyaluronic acid (HA) hydrogel with a chemical gradient of the matrix-linked bisphosphonate (BP) groups is presented. The method consists of two steps, including initial generation of physical gradient patterns of BPs by diffusion of BP acrylamide reagent into HA matrix carrying thiol groups and subsequent chemical immobilization of the BP groups by UV light-triggered thiol-ene addition reaction. This gradient hydrogel permits spatial three-dimensional regulation of secondary interactions of different molecules with the polymer matrix. In particular, graded amounts of cytochrome c (cyt c) were reversibly absorbed in the hydrogel, thus enabling the subsequent spatially controlled release of the therapeutic protein. The obtained patterned hydrogel acts also as a unique reactor in which peroxidase-catalyzed oxidation of a substrate is determined by spatial position of the enzyme (cyt c) in the matrix resulting in a range of product concentrations. As an example, matrix template-assisted oxidation of 3,3',5,5'-tetarmethylbenzydine (TMB) in the presence of H2O2 occurs simultaneously at different rates within the gradient hydrogel. Moreover, calcium binding to the gradient HABP hydrogel reflects the pattern of immobilized BP groups eventually leading to the graded biomineralization of the matrix. This approach opens new possibilities for use of hydrogels as dynamic models for biologic three-dimensional structures such as extracellular matrix.

Classification of fractional order biomarkers for anomalous diffusion using q-space entropy.

In this study, we applied continuous random walk theory (CTRW) to develop a new model that characterizes anomalous diffusion in magnetic resonance imaging experiments. Furthermore, we applied a classification scheme based on information theoretic a techniques to characterize the degree of heterogeneity and complexity in biological tissues. From a CTRW approach, the Fourier transform of the generalized solution to the diffusion equation comes in the form of the Mittag-Leffler function. In this solution form, the relative stochastic uncertainty in the diffusion process can be computed with spectral entropy. We interrogated both white and gray matter regions of a fixed rat brain with diffusion - weighted magnetic resonance imaging experiments up to 26,000 s/mm² by independently weighting q and Δ. to investigate the effects on the diffusion phenomena. Our model fractional order parameters, α and ß, and entropy measure, H(q, Δ), differentiated between tissue types and extracted differing information within a region of interest based on the type of diffusion experiment performed. By combining fractional order modeling and information theory, new and powerful biomarkers are available to characterize tissue microstructure and provide contextual information about the anatomical complexity.

Modeling kinetics and equilibrium of membranes with fields: milestoning analysis and implication to permeation.

Coarse graining of membrane simulations by translating atomistic dynamics to densities and fields with Milestoning is discussed. The space of the membrane system is divided into cells and the different cells are characterized by order parameters presenting the number densities. The dynamics of the order parameters are probed with Milestoning. The methodology is illustrated here for a phospholipid membrane system (a hydrated bilayer of DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) lipid molecules). Significant inhomogeneity in membrane internal number density leads to complex free energy landscape and local maps of transition times. Dynamics and distributions of cavities within the membrane assist the permeation of nonpolar solutes such as xenon atoms. It is illustrated that quantitative and detailed dynamics of water transport through DOPC membrane can be analyzed using Milestoning with fields. The reaction space for water transport includes at least two slow variables: the normal to the membrane plane, and the water density.

Controlled transport of DNA through a Y-shaped carbon nanotube in a solid membrane.

We investigate the possible ratcheting dynamics of double-stranded DNA (dsDNA) driven through a Y-shaped carbon nanotube (Y-CNT) in a solid membrane, using all-atom molecular dynamics (MD) simulation. By applying constant or alternating biasing voltages, we found that the dsDNA molecule can be unzipped at the junction of the Y-CNT. Because of the energy barrier (a few kBT per base-pair), the motion of the entire DNA molecule was alternatively in a trapped state or a transiting state. We show that during each transiting state the same number of nucleotides were transported (DNA ratcheting). An analytical theory that is mathematically equivalent to the one for Josephson junctions was then proposed to quantitatively describe the simulation results. The controlled motion of DNA in the Y-CNT is expected to enhance the accuracy of nanopore-based DNA sequencing.

Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood-brain barrier.

PURPOSE: The present study examines the use of an external magnetic field in combination with the disruption of tight junctions to enhance the permeability of iron oxide nanoparticles (IONPs) across an in vitro model of the blood-brain barrier (BBB). The feasibility of such an approach, termed magnetic field enhanced convective diffusion (MFECD), along with the effect of IONP surface charge on permeability, was examined. METHODS: The effect of magnetic field on the permeability of positively (aminosilane-coated [AmS]-IONPs) and negatively (N-(trimethoxysilylpropyl)ethylenediaminetriacetate [EDT]-IONPs) charged IONPs was evaluated in confluent monolayers of mouse brain endothelial cells under normal and osmotically disrupted conditions. RESULTS: Neither IONP formulation was permeable across an intact cell monolayer. However, when tight junctions were disrupted using D-mannitol, flux of EDT-IONPs across the bEnd.3 monolayers was 28%, increasing to 44% when a magnetic field was present. In contrast, the permeability of AmS-IONPs after osmotic disruption was less than 5%. The cellular uptake profile of both IONPs was not altered by the presence of mannitol. CONCLUSIONS: MFECD improved the permeability of EDT-IONPs through the paracellular route. The MFECD approach favors negatively charged IONPs that have low affinity for the brain endothelial cells and high colloidal stability. This suggests that MFECD may improve IONP-based drug delivery to the brain.